Prognostic Implications of HER-2 Status in Steroid Receptor–Positive, Lymph Node–Negative Breast Carcinoma

Patients with lymph node–negative breast carcinoma (LNNBC) and positive hormone receptor (HR) status during estrogen-based endocrine therapy have different prognoses. The contribution of HER-2 (human epidermal growth factor receptor-2) has not been extensively evaluated. We stained 230 LNNBCs for estrogen and progesterone receptors (ER and PR) and HER-2. HER-2 gene status was studied in 150 randomly selected tumors by chromogenic in situ hybridization and cases with discordant or nondefinitive results by fluorescence in situ hybridization. Patients with ER+ and/or PR+ tumors were treated with tamoxifen. We found positive expression of ER, PR, and HER-2 in 73.7%, 67%, and 27.8%, respectively, and HER-2 amplification in 18.0%. Poorer outcome was seen for patients with ER+ and/or PR+/HER-2 overexpressing tumors and as a trend for patients with HER-2 amplification. ER/PR and HER-2 expression showed an independent prognostic value. In LNNBCs with positive HR status, HER-2 overexpression and/or amplification confer an aggressive tumor phenotype, and this might be related to tamoxifen unresponsiveness. Patients with lymph node–negative breast carcinoma (LNNBC) are considered to have a low risk of disease progression. However, about 10% to 30% of patients treated with only locoregional therapy will have a recurrence. 1 Therefore, the identification of this subset of patients is important for decisions about adjuvant therapy. Women who have tumors with positive hormone receptor (HR) status receive adjuvant endocrine therapy with tamoxifen or aromatase inhibitors, depending on menopausal status. Nevertheless, only a portion will have a response, and with continued treatment, a high proportion of tumors will become unresponsive and will relapse. 2 It is known that steroid hormones have rapid nongenomic effects on cell signaling pathways, but the receptor mechanisms responsible for this, interaction with other factors, and association with the biologic differences in patients are not well defined. 3-9 In the breast, normal ductal epithelium and many malignant tumors are dependent on estrogen for growth and cell survival. This effect is mediated by estrogen receptor (ER), a nuclear transcription factor that binds estrogen as a ligand, induces ER homodimer formation, and activates the promoter of several genes, including progesterone receptor (PR), that induce cell proliferation and confer resistance to apoptosis. Breast cancers that express a high level of ER are, at least initially, responsive to hormonal therapies. 10 On the other hand, PR is an estrogen-regulated gene with an active estrogen-responsive element in its promoter. Therefore, almost all breast cancers that are ER+ are also PR+. The Nterminus of PR mediates a progestin-dependent interaction of PR with various cytoplasmic signaling molecules, including proteins with tyrosine kinase activity, that have an important role in progestin-related growth effects in breast epithelial cells. 7